Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-05, Vol.105 (20), p.7269-7274
• Main Authors: Jazdzewski, Krystian, Murray, Elizabeth L, Franssila, Kaarle, Jarzab, Barbara, Schoenberg, Daniel R, de la Chapelle, Albert
• Format: Article
• Language: English
• Subjects: Alleles; Biological Sciences; Cancer; Carcinoma - etiology; Carcinoma - genetics; Case-Control Studies; Cell Line, Tumor; Cohort Studies; DNA; Gene expression; Genetic mutation; Genetic Predisposition to Disease; Genetics; Genotype; Genotypes; Humans; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - metabolism; Mutation; Papillary carcinoma; Plasmids; Polymorphism; Polymorphism, Single Nucleotide; RNA; Thyroid cancer; Thyroid diseases; Thyroid gland; Thyroid Neoplasms - etiology; Thyroid Neoplasms - genetics; Transfection; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0802682105

Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found. We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decrease in the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC. In an association study of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a common polymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a role in the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through target genes whose expression is affected by the SNP status.